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Melanoma of the uveal tract (iris, ciliary body, and choroid), though rare, is the most common primary intraocular malignancy in adults. The mean age-adjusted incidence of uveal melanoma in the United States is approximately 4.3 new cases per million population. [1] The age-adjusted incidence of this cancer has remained stable for the past 50 years.
Uveal melanoma is diagnosed mostly at older ages, with a progressively rising age-specific incidence rate that peaks near the age of 70. [1] Host susceptibility factors associated with the development of this cancer include Caucasian race, light eye color, fair skin color, and the ability to tan. [1] [2] In view of these susceptibility factors, numerous observational studies have attempted to explore the relationship between sunlight exposure and risk of uveal melanoma. To date, these studies have found only weak associations or yielded contradictory results. [1] Similarly, there is no consistent evidence that occupational exposure to UV light or other agents is a risk factor for uveal melanoma. [1]
Uveal melanomas can arise in the anterior (iris) or the posterior (ciliary body or choroid) uveal tract. Iris melanomas have the best prognosis, whereas melanomas of the ciliary body have the worst. Most uveal tract melanomas originate in the choroid. The ciliary body is less commonly a site of origin, and the iris is the least common. The comparatively low incidence of iris melanomas has been attributed to the characteristic features of these tumors, i.e., they tend to be small, slow growing, and relatively dormant in comparison with their posterior counterparts. Iris melanomas rarely metastasize. [3] Melanomas of the posterior uveal tract are cytologically more malignant, detected later, and metastasize more frequently than iris melanomas. The typical choroidal melanoma is a brown, elevated, dome-shaped subretinal mass. The degree of pigmentation ranges from dark brown to totally amelanotic.
Most uveal melanomas are initially completely asymptomatic. As the tumor enlarges, it may cause distortion of the pupil (iris melanoma), blurred vision (ciliary body melanoma), or markedly decreased visual acuity caused by secondary retinal detachment (choroidal melanoma). Serous detachment of the retina frequently complicates tumor growth. If extensive retinal detachment occurs, secondary angle-closure glaucoma occasionally develops. Clinically, several lesions simulate uveal melanoma, including metastatic carcinoma, posterior scleritis, and benign tumors, such as nevi and hemangiomas. [4]
Careful examination by an experienced clinician remains the most important test to establish the presence of intraocular melanoma. Ancillary diagnostic testing, including fluorescein angiography and ultrasonography, can be extremely valuable in establishing and/or confirming the diagnosis. [5]
A number of factors influence prognosis. The most important are cell type, tumor size, location of the anterior margin of the tumor, the degree of ciliary body involvement, and extraocular extension. Cell type, however, remains the most often used predictor of outcome. [6] The selection of treatment depends on the site of origin (choroid, ciliary body, or iris), the size and location of the lesion, the age of the patient, and whether extraocular invasion, recurrence, or metastasis has occurred. Extraocular extension, recurrence, and metastasis are associated with an extremely poor prognosis, and long-term survival cannot be expected. [7] The 5-year mortality rate caused by metastasis from ciliary body or choroidal melanoma is approximately 30%, compared with a rate of 2% to 3% for iris melanomas. [8] In a group of patients with large tumors of the choroid or choroid and ciliary body, the concurrent presence of abnormalities in chromosomes 3 and 8 was also associated with a poor outcome. [9]
In the past, enucleation (eye removal) was the accepted standard treatment for primary choroidal melanoma, and it remains the most commonly used treatment for large tumors. Because of the effect of enucleation on the appearance of the patient, the diagnostic uncertainty encountered by the ophthalmologist (particularly in the case of smaller tumors), and the potential for tumor spread, alternative treatments, such as radiation therapy (i.e., brachytherapy or external-beam, charged-particle radiation therapy), transpupillary thermotherapy, photocoagulation, and cryotherapy have been developed in an attempt to spare the affected eye and possibly retain useful vision. [10] [11] One of the clinical trials of the randomized Collaborative Ocular Melanoma Study compared iodine 125 (125I) episcleral-plaque brachytherapy to enucleation in treating patients with medium-sized choroidal tumors. [12] Eighty-five percent of the patients treated with 125I brachytherapy retained their eye for 5 years or more, and 37% had visual acuity better than 20/200 in the irradiated eye 5 years after treatment. [12] No significant differences in mortality were observed between the two study arms after 12 years of follow-up, whether considering death from all causes or death with histopathologically confirmed melanoma metastasis. [13]
Primary intraocular melanomas originate from melanocytes in the uveal tract. [1] Four distinct cellular types are recognized in intraocular melanoma (revised Callendar classification): [2]
Most primary intraocular melanomas contain variable numbers of epithelioid, spindle A, and spindle B cells (mixed-cell melanomas). Pure epithelioid-cell primary melanomas are infrequent (approximately 3% of cases). [1] In the Collaborative Ocular Melanoma Study, mixed-cell type melanomas predominated (86% of cases). [3]
Several microscopic features can affect the prognosis of intraocular melanoma, including cell type, mitotic activity, lymphocytic infiltration, and, possibly, fibrovascular loops. [1] Cell type remains the most often used predictor of outcome following enucleation, with spindle A cell melanomas carrying the best prognosis and epithelioid cell melanomas carrying the worst. [1] [4]
Uveal melanoma most often assumes a nodular or dome-shaped configuration, but occasionally tumors can be flat or diffuse and involve extensive areas of the uvea with little elevation.
Tumor size classifications according to boundary lines are as follows:
In clinical practice, the tumor base may be estimated in average optic disc diameters (1 dd = 1.5 mm). The average elevation may be estimated in diopters (3 diopters = 1 mm). Other techniques, such as ultrasonography, should be used to provide more accurate measurements.
An important function of ophthalmic ultrasonography is the detection of extrascleral extension. [5] [6] Extrascleral extension measuring 2 mm or more in thickness can invariably be demonstrated provided it is located behind the equator where the intraocular tumor, sclera, and adjacent orbital fat are readily imaged. [7] Orbital extraocular extension of choroidal melanoma may be found in eyes with medium and large tumors, but it is very rare in eyes with small melanomas.
Because the uveal tract is a vascular structure without lymphatic channels, tumor spread occurs principally by local extension and by dissemination through the blood stream. If regional preauricular, submandibular, or cervical lymph node involvement is seen, subconjunctival extension of the primary tumor has occurred. [8]
Systemic metastases are generally hematogenous in origin, and the first site identified is usually the liver. [9] Lung, bone, and subcutaneous sites are also common. [9] In the Collaborative Ocular Melanoma Study trials, the liver was the only site of detectable metastasis in 46% of patients with metastases reported during follow-up or at the time of death; 43% had metastases diagnosed in the liver and other sites. [9] In patients with a history of ocular melanoma who present with hepatic metastases of unknown origin, metastatic melanoma should be considered in the differential diagnosis.
It is particularly unusual for choroidal melanomas of any size to invade the optic nerve or its meninges. [10] Metastasis of choroidal melanoma to the contralateral choroid is also rare. [9] [11]
An American Joint Committee on Cancer staging system has been developed for melanoma of the uveal tract, [12] and its widespread utilization has been advocated. [13]
Melanocytic stromal proliferations of the iris are the most common tumors of the iris. Clinical differentiation between an iris nevus and a melanoma might sometimes be difficult and at times impossible. Melanomas of the iris are usually small discrete lesions, though occasionally, they may be diffuse, infiltrative, multiple, and they may result in heterochromia, chronic uveitis, or spontaneous hyphema. Iris melanomas that involve more than 66% of the angle circumference are associated with secondary glaucoma. [1]
Routine evaluation of iris melanomas includes gonioscopy, transillumination of the globe, and indirect ophthalmoscopy with 360° of scleral depression. Photographic documentation is essential to document progression in size or growth of the tumor. [2] Anterior segment fluorescein angiography may be helpful to demonstrate the vascularity of the lesion but is not diagnostic. High-resolution ultrasound biomicroscopy can be used to measure small lesions (basal dimensions and thickness) and to assess tumor involvement of the anterior ciliary body, angle, and overlying sclera. [3] The main disadvantage with this technology is its limited penetration of large lesions. In these cases, conventional ultrasonography is more accurate.
In general, iris melanomas have relatively good outcomes, with a 5-year survival rate of more than 95%. Iris melanomas are predominantly of the spindle cell type and are usually smaller in size than posterior melanomas because of earlier detection. Clinical features, including prominent tumor vascularity, rapid growth, and heterogeneous pigmentation, are associated with an epithelioid cell component. [4] Involvement of the iridocorneal angles is frequently associated with ciliary body invasion. [4]
Conservative management is generally advocated whenever possible, but surgical intervention may be justified with unequivocal tumor growth and with extensive disease at initial examination.
Standard treatment options:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with iris melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Melanoma involving the ciliary body is a rare tumor that carries a poor prognosis. This malignancy is often diagnosed late, and in some cases, diagnosis may be difficult because of similarity to other eye diseases. The differential diagnosis of ciliary body melanoma should be considered in cases of unilateral pigmentary glaucoma and chronic uveitis. [1]
Ultrasound biomicroscopy can be used to evaluate tumor shape, thickness, margins, reflectivity, and local invasion. [2] [3] Patients with tumors greater than 7 mm in thickness are at increased risk for metastatic disease and melanoma-related death than patients with thinner tumors. [4]
Standard treatment options:
There are several options for management of ciliary body melanoma. The choice of therapy, however, depends on many factors.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with ciliary body and choroid melanoma, small size. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The natural history of small choroidal melanoma remains poorly understood. Small, pigmented choroidal lesions cannot always be differentiated reliably on examination. Growth is a presumed indicator of malignant potential. [1]
Although patients diagnosed with small choroidal tumors were not eligible for participation in the Collaborative Ocular Melanoma Study, these patients were offered participation in a prospective follow-up study to evaluate the natural history of small lesions. Two-year and 5-year tumor growth estimates of 21% and 31%, respectively, were reported. [2] Clinical risk factors associated with tumor growth included increased tumor thickness, presence of subretinal fluid, orange pigmentation, absence of drusen, absence of retinal pigment, margin at the optic disc, and epithelial changes surrounding the tumor. [2] [3]
The 5-year melanoma-related mortality rate in patients treated for small choroidal melanomas has been reported as high as 12%. [4] [5] Several studies indicate that the two most important clinical factors predictive of mortality are larger tumor size (at the time of treatment) and documentation of tumor growth. [6]
Typical features of the tumor on ophthalmoscopy, fluorescein angiography, and ultrasound examination of the eye contribute to the clinical diagnosis. Accuracy of the tumor thickness measurement by echography is an important issue with very small tumors. Wide-field photography is helpful to detect the rate of choroidal tumor growth. [7] Although these techniques have improved the diagnostic differentiation of larger size melanomas, the accuracy of diagnosis for small melanomas is more uncertain. Furthermore, smaller tumors may not produce symptoms, depending on their location with respect to the macula, and may go undetected unless discovered during the course of a routine eye examination.
The management of small choroidal melanomas is controversial. The likelihood of progression from the time of diagnosis to growth warranting treatment has not been well characterized. In the past, many ophthalmologists advocated observation. This was justified on several grounds, including the difficulty in establishing a correct diagnosis, the lack of any documented efficacy for globe-conserving treatments, and concerns for severe treatment-related morbidity. Some investigators have advocated earlier therapeutic intervention, since smaller tumor size at the time of treatment appears to be associated with lower mortality rates. [3] [8] [9]
The management of choroidal melanomas depends on many factors; most important are tumor size and location. [10] In otherwise healthy patients, a small choroidal melanoma in the posterior fundus is amenable to several treatment options, including radiation therapy, laser photocoagulation, transpupillary thermotherapy, a combination of these methods, or even enucleation. [10] [11] [12] [13]
Standard treatment options:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with ciliary body and choroid melanoma, small size. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Enucleation remains the standard therapy for most large choroidal melanomas and melanomas that cause severe glaucoma or invade the optic nerve. One of the two clinical trials of the Collaborative Ocular Melanoma Study (COMS) compared preoperative external-beam radiation therapy plus enucleation to enucleation alone in patients with large choroidal tumors to address the concern that enucleation might precipitate tumor metastasis and shorten survival. [1] After 10 years of follow-up, the cumulative all-cause mortality rate for each treatment arm was 61%. In addition, the 10-year rates of death with histopathologically confirmed melanoma metastasis were not significantly different (45% in the pre-enucleation radiation arm and 40% in the enucleation-alone arm, P = .40). [1][Level of evidence: 1iiA]
Episcleral radionuclide plaque brachytherapy and external-beam, charged-particle radiation therapy offer patients eye-sparing and vision-sparing alternatives to enucleation. [2] [3] Both treatment approaches result in relatively slow regression of uveal melanoma during a period of 6 months to 2 years. Most tumors regress to approximately 50% of their original thickness; only occasionally does a tumor regress to a completely flat scar. [2] Local control is achieved in a large proportion of treated eyes with either technique. The probability of visual preservation and of eye retention with either method is related to tumor size and location.
Plaque brachytherapy is the most frequently used eye-sparing treatment for choroidal melanoma. Iodine 125 (125I), gold 198 (198Au), palladium 103 (103Pd), and other ophthalmic plaques can be effective in the treatment of medium-sized melanomas. [4] [5] [6] [7] 125I is the most commonly used isotope because of its good tissue penetration, accessibility, adequate shielding of the source, and lesser risk to other ocular structures and medical personnel. Methods to ensure proper plaque placement are critical to successful radiation therapy. [8] [9] [10] [11] [12]
Results from the second COMS clinical trial, which compared 125I plaque brachytherapy to enucleation in patients with medium-sized choroidal tumors, revealed no significant difference in cumulative all-cause mortality between the two study arms at 12 years of follow-up (43% for 125I plaque brachytherapy vs. 41% for enucleation; risk ratio = 1.04; 95% CI, 0.86–1.24). [13][Level of evidence: 1iiA] In addition, the 12-year rates of death with histopathologically confirmed melanoma metastasis did not differ significantly between the 2 study arms (21% in the 125I brachytherapy arm and 17% in the enucleation arm, P = .62). Among the patients treated with 125I brachytherapy, 85% retained their eye for 5 years or more, and 37% had visual acuity better than 20/200 in the irradiated eye 5 years after treatment. [14]
Charged-particle radiation therapy can be performed with a proton beam or helium ions. [15] [16] Some investigators report better tumor control with helium ion irradiation than with 125I episcleral plaque treatment in terms of local tumor control and eye retention; however, more anterior segment complications are found. [15] [17]
Another radiation therapy technique occasionally employed but not as extensively studied is Gamma Knife surgery. Preliminary evidence suggests that Gamma Knife surgery may be a feasible treatment option for medium-sized choroidal melanomas. [18]
Standard treatment options:
Tumor growth pattern is a factor in the therapeutic decision. If there is a diffuse melanoma or if there is extraocular extension, enucleation should be considered, but radiation therapy can be employed for less extensive disease.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with ciliary body and choroid melanoma, medium/large size. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Extrascleral extension usually confers a poor prognosis. For patients with gross tumor involvement of the orbit, treatment requires orbital exenteration often combined with preoperative or postoperative radiation therapy; however, there is no evidence that this radical surgery will prolong life. Most patients with localized or encapsulated extraocular extension are not exenterated. This subject is controversial. [1] [2] [3] [4] [5]
No effective method of systemic treatment has been identified for patients with metastatic ocular melanoma. [6]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with extraocular extension melanoma and metastatic intraocular melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The prognosis for any patient with recurring or relapsing disease is poor, regardless of cell type or stage. The question and selection of further treatment depends on many factors, including the extent of the lesion, age and health of the patient, prior treatment, and site of recurrence, as well as individual patient considerations. Clinical trials are appropriate and should be considered whenever possible.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent intraocular melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added Purpose of This PDQ Summary as a new section.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of intraocular melanoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board. Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Intraocular (Eye) Melanoma Treatment is:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Intraocular (Eye) Melanoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/HealthProfessional. Accessed <MM/DD/YYYY>.
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